Heterogeneity of collagen and collagen-fibronectin networks promotes invasive behavior of liver cancer cells

Purpose The remodeling of the extracellular matrix (ECM) is a key feature of tumor development in the liver, particularly in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Fibrosis and cirrhosis are risk factors for tumorigenesis and define serious structural changes in the ECM. Fibrotic-induced collagen and fibronectin alter the stiffness and heterogeneity of the ECM. A stiffened and heterogeneous ECM promotes the proliferation, migration, and invasion of tumor cells. Direct effects of structural changes in the ECM on HCC / iCCA cancer cells are insufficiently studied. Methods HCC and iCCA cells were examined in contact with varying structurally heterogeneous collagen and collagen-fibronectin networks. Heterogeneity of the networks was defined by the combination of stiffness and intrinsic properties. Network heterogeneity-related effects of cell-matrix interactions on cell stiffness, invasiveness, and the ability to interact with network structures by fiber displacements were determined. Results Increased network heterogeneity caused a decrease in cell stiffness, an increase in cell invasiveness, and altered fiber displacements. Different effects on HCC and iCCA cells depending on network heterogeneity were identified. High ECM heterogeneity resulted in low cell stiffness and high cell invasion across cancer cell types. Conclusions We present a model system that is applicable to identify structurally induced influences of the extracellular matrix on cancer cells and to investigate the risk factor of structural changes in the tumor environment.